Synthesizing 1-(4-chlorophenyl)-N-phenylmethanimine, working the Ethanol Solvent based Reaction, and Open Source Science
Mark Mangir
Department of Chemistry
Drexel University
Philadelphia, PA 19104
For completion of Senior Research, June 2012
Abstract:
The goal of the experiments conducted within this paper were: 1) To synthesize the 1-(4-chlorophenyl)-N-phenylmethanimine product, 2) determine the conditions that led Evan Curtin to produce a significant amount of Benzoic Acid rather than the desired imine product, 3) test the solubility of 1-(4-chlorophenyl)-N-phenylmethanimine in a variety of solutions, so that data for it can be entered into the ONS database, and 4) to conduct research in an open source manner including methods such as Wikispaces. Pure 1-(4-chlorophenyl)-N-phenylmethanimine product has been obtained, without the significant acid side product that Evan had encountered. The procedure was not changed significantly, except that a strict 1:1 aldehyde to amine ratio has been enforced. The reason for Evan's significant amount of Benzoic acid product has not yet been determined, since the data using his established method has not been able to be reproduced. The solubility of 1-(4-chlorophenyl)-N-phenylmethanimine has been tested in 5 solvents: ethanol, acetonitrile, benzene, hexane and THF. To promote an open and public discussion of experimental data, all of these research has been available to the public via the usefulchem and ONSchallenge wikispace pages. Online spectra were made possible by converting the NMR spectra into the JCAMP format utilizing a program developed by Robert Lancashire, uploaded onto a Drexel server and linked to on the main experiment wiki page.
Introduction:
The main focus of this research project initially was to determine the source of oxidation that led Evan Curtin's experiments to form a significant portion of benzoic acid as his final product. The reaction was between a 1:1 molar ratio of 4-chlorobenzaldehyde and aniline in ethanol. The reaction was let to sit overnight, and then the solution was vacuum filtered and wash with a small portion of ethanol. By literature(1), the reaction should produce a pure 99% yield, but Evan's yield was prodominently benzoic acid rather than the expected imine product.
There were originally three possible theories for how the oxidation occurred. The first theory tested was that it was the excess of amine in Evan's experiments, a 1:2 aldehyde to amine ratio rather than the given 1:1 ratio, cause the oxidation. The second theory was that it was the fact that Evan's reagents were not dissolved properly. The paper had reported that both reactants dissolved readily in ethanol, but the 4-chloro-b would not dissolve for him, he was required heating and the use of a sonicator to make even a large portion, but not all, dissolve into the ethanol solvent. The final theory was that the 4-chlorobenzaldehyde created a hemi-acetal with the ethanol, and this went on to oxidize into the benzoic acid that was seen in Evan's final product.
Once the correct synthesis procedure had been established, the imine was tested for solubility in a variety of solvents including ethanol, acetonitrile, benzene, hexane, and THF. This data has been uploaded onto the ONS Challenge wikispace for use by anyone who accesses the site.
Experimental:
Basic Imine Preparation Procedure
The Imine compound was synthesized by a general method with slight variations. First, the solid aldehyde was added to the test tube, followed by the liquid amine, and finally the solvent was added. The test tubes were inverted until all of the reactants had dissolved.
Variations to the Procedure
Originally, four samples using ethanol as the solvent had been started in UC EXP276, but only the 1:1 ratio sample made it to completion. This was due to time constraints caused by the fact that NMR with ethanol in the sample had given unusable spectra, and the first sample took two weeks to dry on our rotovap without vacuum or heating. The dried sample was then washed with ethanol and prepared for NMR in CDCl3.
UC EXP277 is the only reaction that was performed in methanol, since the previous attempts to dissolve the reactants in ethanol had required additional measures not included in the original procedure. In this attempt the reactants dissolved correctly, the only difficult was the NMR of the sample was delayed one week due to a problem which did not allow the 300MHz NMR to lock on the sample.
UC EXP278 was once again performed in ethanol, after Stephanie Costa had done a solubility study of the 4-chloro-benzaldehyde in ethanol (ONS EXP258)and had determined that a solution of at least 2M could be obtained without having the reactant come out of solution. In this experiment 1:1, 2:1, and 1:2 ratios of aldehyde to amine were tested, and NMR were obtained after 15 minutes, 1 hour, and overnight to test the kinetics of the reaction. It was attempted to obtain dried samples from this experiment, but the concentrations had been so low that all the product was dissolved by the wash.
UC EXP279also was performed in ethanol with the same ratios as UC EXP278, but at double the concentration.
Heat Dissolve Method
A known amount of the imine was placed in a screw capped vial. Next an approximately measured amount of the chosen solvent was added to the vial. The vial was completely wrapped in parafilm and placed in a water bath that was at approximately 45C for 15 minutes. The samples were then removed from the water bath and let sit in the hood to cool back to room temperature. At this point a small sample of the supernatant was removed, and an NMR was taken.
Shake Dissolve Method
A known amount of the imine was placed in a screw capped vial. Next an approximately measured amount of the chosen solvent was added to the vial. The vial was completely wrapped in parafilm and placed on a shake plate for at least 24 hours. The samples were then removed from the shake plate, and a small sample of the supernatant was removed, and an NMR was taken.
Results:
The first two attempts at preparing the reaction (UC EXP 276 and 277) the reactants had shown similar results to those received by Evan. The washed sample prepared in experiment 276 seemed to be purely acid, and actually had no trace of the desired imine. The product achieved in Useful Chem Exp 277 was clearly a mixture of Imine and Acid. This may have been due to the fact that the aldehyde more readily forms a hemi-acetal with methanol, since this combination of both products was not repeated in any other sample.
UC EXP278 was meant to be a kinetic study, but since the solution was mixed with CDCL3 for the duration of the experiment it was concluded to not be an accurate rate measurement for the reaction. On the other hand, it was determined that as the reaction progressed the aldehyde peak did diminish, showing that the reaction was taking place. The NMR from all of these samples showed a large predominance of the imine product, and an almost negligible amount of acid product. This showed promise that the literature may have been correct, and some variation caused the acid formation.
UC EXP279 was a repeat of the previous experiment at double the concentration. The NMR spectra of these samples showed pure imine product with no trace of the acid product. This leads me to believe that the literature procedure was correct.
UC EXP280's major goal was to produce enough imine product so that I would not need to prepare anymore before the conclusion of this project, but NMR samples were obtained to validate that the imine product had been obtained. The NMR of both large batches matched the previous data.
Two sets of solubility data was obtained between ONS EXP272 and ONS EXP297. The first experiment(272) was done using the heat dissolve method, while the second experiment was performed using the shake dissolve method. The solubility in ethanol was almost exactly the same in both experiments. It was 0.379M in ONS EXP272, compared to 0.378M in ONS EXP297. The value for acetonitrile was off, it was 1.321M in the first experiment and 0.978M in the second. They were off by 26%. It is possible the solution was not as saturated as it could have been. The value for benzene was close, it was 2.273M in the first experiment and 2.493M in the second, off by 8.8%. The value for hexane was 0.105M in the second eperiment, this was the first and only piece of data for the imine in hexane. Lastly, the value for THF was kind of close, it was 3.149M in the first experiment and 3.765M in the second, off by 16.4%.
ONS EXP287 was performed by the heat dissolve method to test the solubility in a variety of ethylene glycol based solvents. Unfortunately, it was discovered during this process that the heat dissolve method does not work for these solvents because of their high viscosity. This is evidenced by the extremely low measured solubility in ethylene glycol of 0.018M. Due to time constraints a shake dissolve method sample was never run.
Conclusions:
At first it seemed that Evan's determination had been correct, and that this procedure produced Benzoic Acid in a significant quantity, as well as the desired Imine product. But as I became more proficient in the procedure, the acid, while still formed, was only an insignificant product of this reaction. It seems that some other factor forced the reaction towards the formation of the acid. It has been concluded that this driving force was not the concentration of the amine, since Exp 278 and 279 both ran 1:2 aldehyde to amine concentrations, same as Evan's, and only produced an insignificant amount of acid.
While no accurate determination has been made at this time, I have a couple of hypotheses. It could be heat in the reaction that had caused this acid product. The first two experiments I ran had been slightly heated by being left long enough in the sonicator that the water temperature had risen noticeably. Evan had also used the sonicator in his experiments to help the aldehyde dissolve into the ethanol. It is also possible that the excess of the imine helped drive the reaction in that direction. The 1:2 aldehyde to amine ratio products had consistently higher percentage of acid product, but still none nowhere near the amount recovered by Evan.
For low viscosity solvents there is no real difference between the heat dissolve method and the shake dissolve method, especially proved by the almost identical molarity obtained by the samples dissolved in ethanol. On the other hand, for high viscosity solvents, the shake dissolve method is the only way to obtain an accurate saturated molarity.
Future Work:
It has been proven that using the method provided it is possible to make a 99% pure 1-(4-chlorophenyl)-N-phenylmethanimine product, without losing a significant portion to the benzoic acid byproduct. Using this product a general solubility of cyclic ring imines in the chosen ethylene glycol based solvents can be obtained. Also, the exact reason for the large amount of acid formation was never truly determined, but without being able to reproduce Evan's data that feat may prove impossible.
Reference List
1. Blanco-Ania, Daniel, Et Al. "Synthesis of Cucurbitine Derivatives: Facile Straightforward Approach to Methyl 3-amino-4-aryl-1-methylpyrrolydine-3-carboxylates." ScienceDirect.com, 24 Apr. 2009. Web. 15 June 2012. <http://www.sciencedirect.com/science/article/pii/S0040402009006231>.
2. Costa, Stephanie. EXP258, ONS Challenge Blog February 25, 2012 http://onschallenge.wikispaces.com/EXP258
3. Curtin, Evan. EXP262, Useful Chem Blog March 8, 2011 http://usefulchem.wikispaces.com/Exp262
4. Kamura, Masakazu, Et Al. "Synthesis and Investigation of π-conjugated Azomethine Self-assembled Multilayers by Layer-by-layer Growth." ScienceDirect.com, 11 Mar. 2010. Web. 15 June 2012. <http://www.sciencedirect.com/science /article/pii/S0040609010003019>.
5. Liao, Wenyan. "1,2,3-Triazole-boranes: Stable and Efficient Reagents for Ketone and Aldehyde Reductive Amination in Organic Solvents or in Water." Chemical Communications, 28 Sept. 2009. Web. 15 June 2012. <http://pubs.rsc.org/en/Content/ArticleLanding/2009/CC/b915361f>.
6. Neuvonen, K, Et Al. "Comparison of the Electronic Structures of Imine and Hydrazone Side-Chain Functionalities with the Aid of 13C and 15N NMR Chemical Shifts and PM3 Calculations. The Influence of CN-Substitution on the Sensitivity to Aromatic Substitution." The Journal of Organic Chemistry, 25 Feb. 2003. Web. 15 June 2012. <http://pubs.acs.org/doi/full/10.1021/jo020608l>.
Synthesizing 1-(4-chlorophenyl)-N-phenylmethanimine, working the Ethanol Solvent based Reaction, and Open Source Science
Abstract:
The goal of the experiments conducted within this paper were: 1) To synthesize the 1-(4-chlorophenyl)-N-phenylmethanimine product, 2) determine the conditions that led Evan Curtin to produce a significant amount of Benzoic Acid rather than the desired imine product, 3) test the solubility of 1-(4-chlorophenyl)-N-phenylmethanimine in a variety of solutions, so that data for it can be entered into the ONS database, and 4) to conduct research in an open source manner including methods such as Wikispaces. Pure 1-(4-chlorophenyl)-N-phenylmethanimine product has been obtained, without the significant acid side product that Evan had encountered. The procedure was not changed significantly, except that a strict 1:1 aldehyde to amine ratio has been enforced. The reason for Evan's significant amount of Benzoic acid product has not yet been determined, since the data using his established method has not been able to be reproduced. The solubility of 1-(4-chlorophenyl)-N-phenylmethanimine has been tested in 5 solvents: ethanol, acetonitrile, benzene, hexane and THF. To promote an open and public discussion of experimental data, all of these research has been available to the public via the usefulchem and ONSchallenge wikispace pages. Online spectra were made possible by converting the NMR spectra into the JCAMP format utilizing a program developed by Robert Lancashire, uploaded onto a Drexel server and linked to on the main experiment wiki page.
Introduction:
The main focus of this research project initially was to determine the source of oxidation that led Evan Curtin's experiments to form a significant portion of benzoic acid as his final product. The reaction was between a 1:1 molar ratio of 4-chlorobenzaldehyde and aniline in ethanol. The reaction was let to sit overnight, and then the solution was vacuum filtered and wash with a small portion of ethanol. By literature(1), the reaction should produce a pure 99% yield, but Evan's yield was prodominently benzoic acid rather than the expected imine product.
There were originally three possible theories for how the oxidation occurred. The first theory tested was that it was the excess of amine in Evan's experiments, a 1:2 aldehyde to amine ratio rather than the given 1:1 ratio, cause the oxidation. The second theory was that it was the fact that Evan's reagents were not dissolved properly. The paper had reported that both reactants dissolved readily in ethanol, but the 4-chloro-b would not dissolve for him, he was required heating and the use of a sonicator to make even a large portion, but not all, dissolve into the ethanol solvent. The final theory was that the 4-chlorobenzaldehyde created a hemi-acetal with the ethanol, and this went on to oxidize into the benzoic acid that was seen in Evan's final product.
Once the correct synthesis procedure had been established, the imine was tested for solubility in a variety of solvents including ethanol, acetonitrile, benzene, hexane, and THF. This data has been uploaded onto the ONS Challenge wikispace for use by anyone who accesses the site.
Experimental:
Basic Imine Preparation Procedure
The Imine compound was synthesized by a general method with slight variations. First, the solid aldehyde was added to the test tube, followed by the liquid amine, and finally the solvent was added. The test tubes were inverted until all of the reactants had dissolved.Variations to the Procedure
Originally, four samples using ethanol as the solvent had been started in UC EXP276, but only the 1:1 ratio sample made it to completion. This was due to time constraints caused by the fact that NMR with ethanol in the sample had given unusable spectra, and the first sample took two weeks to dry on our rotovap without vacuum or heating. The dried sample was then washed with ethanol and prepared for NMR in CDCl3.UC EXP277 is the only reaction that was performed in methanol, since the previous attempts to dissolve the reactants in ethanol had required additional measures not included in the original procedure. In this attempt the reactants dissolved correctly, the only difficult was the NMR of the sample was delayed one week due to a problem which did not allow the 300MHz NMR to lock on the sample.
UC EXP278 was once again performed in ethanol, after Stephanie Costa had done a solubility study of the 4-chloro-benzaldehyde in ethanol (ONS EXP258)and had determined that a solution of at least 2M could be obtained without having the reactant come out of solution. In this experiment 1:1, 2:1, and 1:2 ratios of aldehyde to amine were tested, and NMR were obtained after 15 minutes, 1 hour, and overnight to test the kinetics of the reaction. It was attempted to obtain dried samples from this experiment, but the concentrations had been so low that all the product was dissolved by the wash.
UC EXP279also was performed in ethanol with the same ratios as UC EXP278, but at double the concentration.
Heat Dissolve Method
A known amount of the imine was placed in a screw capped vial. Next an approximately measured amount of the chosen solvent was added to the vial. The vial was completely wrapped in parafilm and placed in a water bath that was at approximately 45C for 15 minutes. The samples were then removed from the water bath and let sit in the hood to cool back to room temperature. At this point a small sample of the supernatant was removed, and an NMR was taken.Shake Dissolve Method
A known amount of the imine was placed in a screw capped vial. Next an approximately measured amount of the chosen solvent was added to the vial. The vial was completely wrapped in parafilm and placed on a shake plate for at least 24 hours. The samples were then removed from the shake plate, and a small sample of the supernatant was removed, and an NMR was taken.Results:
The first two attempts at preparing the reaction (UC EXP 276 and 277) the reactants had shown similar results to those received by Evan. The washed sample prepared in experiment 276 seemed to be purely acid, and actually had no trace of the desired imine. The product achieved in Useful Chem Exp 277 was clearly a mixture of Imine and Acid. This may have been due to the fact that the aldehyde more readily forms a hemi-acetal with methanol, since this combination of both products was not repeated in any other sample.
UC EXP278 was meant to be a kinetic study, but since the solution was mixed with CDCL3 for the duration of the experiment it was concluded to not be an accurate rate measurement for the reaction. On the other hand, it was determined that as the reaction progressed the aldehyde peak did diminish, showing that the reaction was taking place. The NMR from all of these samples showed a large predominance of the imine product, and an almost negligible amount of acid product. This showed promise that the literature may have been correct, and some variation caused the acid formation.
UC EXP279 was a repeat of the previous experiment at double the concentration. The NMR spectra of these samples showed pure imine product with no trace of the acid product. This leads me to believe that the literature procedure was correct.
UC EXP280's major goal was to produce enough imine product so that I would not need to prepare anymore before the conclusion of this project, but NMR samples were obtained to validate that the imine product had been obtained. The NMR of both large batches matched the previous data.
Two sets of solubility data was obtained between ONS EXP272 and ONS EXP297. The first experiment(272) was done using the heat dissolve method, while the second experiment was performed using the shake dissolve method. The solubility in ethanol was almost exactly the same in both experiments. It was 0.379M in ONS EXP272, compared to 0.378M in ONS EXP297. The value for acetonitrile was off, it was 1.321M in the first experiment and 0.978M in the second. They were off by 26%. It is possible the solution was not as saturated as it could have been. The value for benzene was close, it was 2.273M in the first experiment and 2.493M in the second, off by 8.8%. The value for hexane was 0.105M in the second eperiment, this was the first and only piece of data for the imine in hexane. Lastly, the value for THF was kind of close, it was 3.149M in the first experiment and 3.765M in the second, off by 16.4%.
ONS EXP287 was performed by the heat dissolve method to test the solubility in a variety of ethylene glycol based solvents. Unfortunately, it was discovered during this process that the heat dissolve method does not work for these solvents because of their high viscosity. This is evidenced by the extremely low measured solubility in ethylene glycol of 0.018M. Due to time constraints a shake dissolve method sample was never run.
Conclusions:
At first it seemed that Evan's determination had been correct, and that this procedure produced Benzoic Acid in a significant quantity, as well as the desired Imine product. But as I became more proficient in the procedure, the acid, while still formed, was only an insignificant product of this reaction. It seems that some other factor forced the reaction towards the formation of the acid. It has been concluded that this driving force was not the concentration of the amine, since Exp 278 and 279 both ran 1:2 aldehyde to amine concentrations, same as Evan's, and only produced an insignificant amount of acid.
While no accurate determination has been made at this time, I have a couple of hypotheses. It could be heat in the reaction that had caused this acid product. The first two experiments I ran had been slightly heated by being left long enough in the sonicator that the water temperature had risen noticeably. Evan had also used the sonicator in his experiments to help the aldehyde dissolve into the ethanol. It is also possible that the excess of the imine helped drive the reaction in that direction. The 1:2 aldehyde to amine ratio products had consistently higher percentage of acid product, but still none nowhere near the amount recovered by Evan.
For low viscosity solvents there is no real difference between the heat dissolve method and the shake dissolve method, especially proved by the almost identical molarity obtained by the samples dissolved in ethanol. On the other hand, for high viscosity solvents, the shake dissolve method is the only way to obtain an accurate saturated molarity.
Future Work:
It has been proven that using the method provided it is possible to make a 99% pure 1-(4-chlorophenyl)-N-phenylmethanimine product, without losing a significant portion to the benzoic acid byproduct. Using this product a general solubility of cyclic ring imines in the chosen ethylene glycol based solvents can be obtained. Also, the exact reason for the large amount of acid formation was never truly determined, but without being able to reproduce Evan's data that feat may prove impossible.
Reference List
1. Blanco-Ania, Daniel, Et Al. "Synthesis of Cucurbitine Derivatives: Facile Straightforward Approach to Methyl 3-amino-4-aryl-1-methylpyrrolydine-3-carboxylates." ScienceDirect.com, 24 Apr. 2009. Web. 15 June 2012. <http://www.sciencedirect.com/science/article/pii/S0040402009006231>.
2. Costa, Stephanie. EXP258, ONS Challenge Blog February 25, 2012 http://onschallenge.wikispaces.com/EXP258
3. Curtin, Evan. EXP262, Useful Chem Blog March 8, 2011 http://usefulchem.wikispaces.com/Exp262
4. Kamura, Masakazu, Et Al. "Synthesis and Investigation of π-conjugated Azomethine Self-assembled Multilayers by Layer-by-layer Growth." ScienceDirect.com, 11 Mar. 2010. Web. 15 June 2012. <http://www.sciencedirect.com/science /article/pii/S0040609010003019>.
5. Liao, Wenyan. "1,2,3-Triazole-boranes: Stable and Efficient Reagents for Ketone and Aldehyde Reductive Amination in Organic Solvents or in Water." Chemical Communications, 28 Sept. 2009. Web. 15 June 2012. <http://pubs.rsc.org/en/Content/ArticleLanding/2009/CC/b915361f>.
6. Neuvonen, K, Et Al. "Comparison of the Electronic Structures of Imine and Hydrazone Side-Chain Functionalities with the Aid of 13C and 15N NMR Chemical Shifts and PM3 Calculations. The Influence of CN-Substitution on the Sensitivity to Aromatic Substitution." The Journal of Organic Chemistry, 25 Feb. 2003. Web. 15 June 2012. <http://pubs.acs.org/doi/full/10.1021/jo020608l>.